Project Summary/Abstract Ozone (O3) is a widespread air toxicant that has detrimental effects on human health. O3 exposure has recently been associated with Alzheimer's disease (AD), and is also associated with AD-related syndromes including cognitive impairment and depression. Rodent studies indicate that both acute and chronic O3 exposure can damage the hippocampus, a brain region important for learning and memory and affected in AD and depression. Further, O3 exposure impairs learning and memory in a mouse model of AD. Despite these data implicating O3 as a neurotoxicant and potential contributor to AD, it is presently not well understood how O3 exerts its effects on the CNS. Since direct oxidative reactions of O3 are limited to the airway, it has been proposed that CNS effects of O3 exposure are stimulated by circulating mediators that are induced in response to pulmonary damage. However, the identity of such mediators remains to be determined. Our preliminary work has identified the acute phase protein, serum amyloid A (SAA), as a potential mediator of O3-induced CNS dysfunction. Acute phase SAA is predominantly made by the liver and secreted into blood following systemic insults, and we have found that O3 markedly induced SAA upregulation in liver and blood 24 hours following O3 exposure in mice. Blood levels of SAA post-ozone exposure highly correlate with measures of pulmonary inflammation, suggesting a causal relationship. We also observed increased protein levels of SAA in the CNS following O3 exposure that were not attributed to local synthesis, and that SAA can cross the intact mouse blood-brain barrier, with particularly high rates of transport into the hippocampus. Elevated SAA in blood has been reported in major depression, and a recent study showed that hepatic overexpression of SAA caused depression-associated behaviors in mice. Depression is a risk factor for AD, and many AD patients also present with major depression. Further, depressed patients typically present with some degree of cognitive impairment. SAA is also elevated in the blood and brains of patients with AD, and so may be a common mediator in both conditions. We hypothesize that O3-induced lung inflammation results in elevated blood levels of liver-derived SAA that acts directly on brain to induce behaviors that are associated with depression and cognitive impairment. In this R21, two aims are proposed to test key aspects of this hypothesis in mice. Aim 1 will determine statistical correlations among levels of lung inflammation, liver, blood, & brain levels of SAA, measures of stress-coping, anhedonia, and spatial memory. Aim 2 will test whether blockade of lung inflammation attenuates the O3-induced elevations of SAA in liver, blood, and brain. Results from this study will provide insight on CNS endpoints likely to be affected by SAA, and mechanisms for SAA increases. Positive results would justify future studies on SAA as a mediator of O3- induced behavioral phenotypes related to AD, providing the preliminary data needed for an RO-1.